Reversible O–H Bond Activation by Tripodal tris(Nitroxide) Aluminum and Gallium Complexes

Herein, we report the preparation and characterization of the Group 13 metal complexes of a tripodal tris(nitroxide)-based ligand, designated (TriNOx3–)M (M = Al (1), Ga (2), In (3)). Complexes 1 and 2 both activate the O–H bond of a range of alcohols spanning a ∼10 pKa unit range via an element-ligand cooperative pathway to afford the zwitterionic complexes (HTriNOx2–)M–OR. Structures of these alcohol adduct products are discussed. We demonstrate that the thermodynamic and kinetic aspects of the reactions are both influenced by the identity of the metal, with 1 having higher reaction equilibrium constants and proceeding at a faster rate relative to 2 for any given alcohol. These parameters are also influenced by the pKa of the alcohol, with more acidic alcohols reacting both to more completion and faster than their less acidic counterparts. Possible mechanistic pathways for the O–H activation are discussed.


Electronic Supplementary Information
Author contribution statement S3 Protocol for the van't Hoff experiment of 1 + t-BuOH.S20 Protocol for determining the K eq values for the reactions of 1 and 2 with various alcohols S20 Procedure for the calculations to give the predicted-pK a of alcohols in DMSO.S36 Table S1.Raw calculated Gibbs standard free energies at 298 K of alcohols and their corresponding alkoxides.S37 Table S2.Calculated standard Gibbs free energies of deprotonation (ΔG deprot ) in DMSO for alcohols and the manipulation of that data to give predicted pK a values for alcohols.S38 Procedure for the calculations to determine the A-values for the alcohol R groups.S40 Table S3.Calculated standard Gibbs free energies at 298 K of the equatorial (ΔG 0 equatorial ) and axial (ΔG 0 axial ) conformers of R-substituted cyclohexanes and the calculated A-values for the R groups.S40 Figure S34.Plot of the pK eq of the reaction of 2 with alcohol versus the A-value of the alcohol R group.S41 Author contribution statement.J.S.S. contributed to the synthesis of 1 and 2 and carried out the Gutmann-Beckett experiments; carried out the reactivity studies between 1 and 2 with alcohols; developed the syntheses and contributed to the characterization of 4, 6, 8 and 9, including all VT-NMR experiments; carried out all K eq and kinetic experiments; conducted calculations to determine alcohol pK a values and R group A-values; drafted and revised the manuscript.M.L.M. contributed to the synthesis of 1 and 2; carried out preliminary reactivity studies of 1 and 2 with alcohols; contributed to the synthesis and characterization of 4, 8, and 9; contributed to the calculations to determine alcohol pK a values; proposed mechanistic considerations.A.J.W. contributed to the synthesis of 1-3; carried out preliminary reactivity studies of 1 and 2 with alcohols.V. W. G. contributed to the synthesis of 1 and 2; contributed to the synthesis and characterization of 4, 6, 8 and 9. A.R.C. contributed to the synthesis of 1 and 2; helped in the drafting and revising of the manuscript.M. R. G. conducted x-ray crystallography.P. R. R. supervised the calculations to determine alcohol pK a values and R group A-values.C.R.G. supervised and administered all aspects of the project and drafted and revised the manuscript.~5 mg of complex was dissolved in ~0.75 mL of NMR solvent (C 6 D 6 for 4; CDCl 3 for 6 and 8).The solution was transferred into an NMR tube equipped with a Teflon J. Young valve and the sample was allowed to equilibrate at 293 K and a 1H NMR spectrum was collected.Then, 1 H NMR spectra were recorded at 303K, 313K, 323K, 333K, 343K, and 353K; before each collection, the sample was allowed to thermally equilibrate for 30 min and then the sample was shimmed prior to collection of the spectra.Protocol for the van't Hoff experiment of 1 + t BuOH: Into a vial was added 500 µL of a 9 mM stock solution of 1 in C 6 D 6 along with 125 µL of a 6 mM stock solution of hexamethylcyclotrisiloxane as an internal standard, also in C 6 D 6 .Then, 125 µL of a 36 mM solution of tert-butanol in C 6 D 6 was added and the reaction was allowed to stir at room temperature for 24 h.The reaction mixture was then transferred to a J-young capped NMR tube and loaded into the NMR spectrometer. 1 H NMR spectra were collected at each indicated temperature.In all cases, the reaction was allowed to thermally equilibrate at the given temperature for 30 min prior to collection of the spectra.The concentration of the metal complexes 1 and 4 were determined by comparison of the integrations of the resonances for the tBu and diasteriotopic CH 2 protons of the TriNOx ligands in each complex relative to internal standard.K eq values were calculated according to the formula: Protocol for the determining the K eq values for the reactions of 2 with alcohols.For each experiment, 500 µL of a 9 mM stock solution of 2 in CDCl 3 was dispensed into a vial along with 125 µL of a 6 mM stock solution of hexamethylcyclotrisiloxane as an internal standard also in CDCl 3 .Then, 125 µL of a 36 mM stock solution of the appropriate alcohol in CDCl 3 was dispensed into the vial.The reaction was allowed to stir at room temperature for 24 hours after which the reaction was transferred to an NMR tube and analyzed by 1 H NMR spectroscopy.K eq values were calculated according to the formula: The concentration of the metal complexes were determined by comparison of the integrations of the ligand NMR signatures to internal standard.For 2 the concentration was taken as the average value determined from comparison to the tBu groups as well as both diastereotopic protons of the bridgehead CH 2 groups.The concentration of the (HTriNOx 2-)Ga-OR complexes were similarly determined by the average of the value found for the tBu groups as well as both diastereotopic protons of the bridgehead CH 2 groups, as well as with any easily identifiable NMR handles in the R group of the resultant alkoxide ligand.The concentration of unreacted alcohol was assumed to be equal to that unreacted complex 2.          Procedure for the calculations to give the predicted-pK a of alcohols in DMSO.All optimization and frequency calculations were performed with the Gaussian '16, Revision B.01 program using the G4 method 1 implementing a SCRF polarizable continuum solvent model of DMSO (ε = 46.826).
Predicted pK a values were determined by calculating the Gibbs standard free energies for the alcohols and their corresponding alkoxide conjugate bases (Table S1).The difference of these energies for each alcohol/alkoxide pair represents the ΔG 0 of deprotonation (ΔG 0 deprot ) for each alcohol (Table S2).The ΔG 0 deprot values across the range of alcohols were normalized to 2,2,2-trifluoroethanol (ΔG 0 deprot,ref ) and then converted to their corresponding calculated pK a values via the following formula: where C is equal to [1.9872 cal/K•mol * 298.15K * [ln(10)/1000].These values represent the pK a of the alcohols relative to 2,2,2-trifluoroethanol and although the absolute values hold no meaning, their relative values can be compared.To do so, we generated a calibration curve (Figure S38) between these calculated pK a values and the pK a values listed in the Bordwell literature for any alcohol with the latter value being available in DMSO .The line-of-best-fit equation was then used to determine the predicted pK a values.Table S2 lists these predicted pK a values for the range of alcohols studied along with the values from the Bordwell literature.2Procedure for the calculations to determine the A-values for the alcohol R groups.All optimization and frequency calculations were performed with the Gaussian '16, Revision B.01 program using the G4 method.REF The geometries of both axial and equatorial conformers of the R-substituted cyclohexanes for each alcohol R group were optimized and the standard Gibbs free energy (ΔG 0 , in kcal/mol) values were calculated.The A-value for a given R substituent is a measurement of how much the equatorial conformer of the R-substituted cyclohexane is favored over the axial conformer.The A-values are thus obtained by subtracting ΔG 0 equatorial from ΔG 0 axial .
Table S3.Calculated standard Gibbs free energies at 298 K of the equatorial (ΔG 0 equatorial ) and axial (ΔG 0 axial ) conformers of R-substituted cyclohexanes and the calculated A-values for the R groups.

Figure S33 .
Figure S33.Correlation plot between the G4-calculated versus experimental determined pK a values for alcohols.S39

Figure S15 .
Figure S15.Stacked plot of the 31 P{ 1 H} NMR spectra of the mixtures of Et 3 PO (i) and Et 3 PS (ii) experiments run to evaluate the Lewis acidity of complexes 1 and 2.

Figure S16 .
Figure S16.Diastereotopic proton region of the 1 H NMR spectra of the 4, 6, and 8 complexes over the temperature range 293-353 K.The samples all contain diethyl ether (marked with an *) that remains throughout the experiment.

Figure S17. 1 H
Figure S17. 1 H NMR spectrum of a 1:1 mixture of 1:t-BuOH.Taken in C 6 D 6 and recorded after 24 hours of stirring at room temperature.

Figure S18. 1 HS22FigureS23FigureS26Figure
Figure S18. 1 H NMR spectrum of a 1:1 mixture of 1:t-BuOH.Taken in CDCl 3 and recorded after 24 hours of stirring at room temperature.

Figure S30 .
Figure S30. 1 H NMR spectra of the reaction of t-BuSH with 1 (i) and 2 (ii) in C 6 D 6 recorded after 24 hours of stirring at room temperature.Resonances for the presumptive (HTriNOx 2-)Ga-S t Bu product are labeled with an *. i.s.= internal standard = hexamethylcyclotrisiloxane

Figure S31 .
Figure S31.Plot showing the concentration of products over time for the reaction of 1 and 2 with i-PrOH in C 6 D 6 at 20 °C.

Figure S32 .
Figure S32.Initial rate data for the reaction of 2 with i-PrOH in C 6 D 6 at 20 °C.Replicate trials are represented by blue, black, and red lines.

Figure S33 .
Figure S33.Correlation plot between the G4-calculated versus experimental determined pK a values for alcohols.

Figure S34 .
Figure S34.Plot of the pK eq of the reaction of 2 with alcohol versus the A-value of the alcohol R group.

Table S1 .
Raw calculated Gibbs standard free energies at 298 K of alcohols and their corresponding alkoxides.

Table S2 .
Calculated standard Gibbs free energies of deprotonation (ΔG deprot ) in DMSO for alcohols and the manipulation of that data to give predicted pK a values for alcohols.Values are quoted in DMSO and taken from Reich, H. Bordwell pK a Table.https://organicchemistrydata.org/hansreich/resources/pka/.